Longitudinal noninvasive imaging of progesterone receptor as a predictive biomarker of tumor responsiveness to estrogen deprivation therapy.

Abstract

PURPOSE:

To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [(18)F]FDG (to measure glucose uptake), [(18)F]FES [to measure estrogen receptor (ER) levels], or [(18)F]FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogen-deprivation therapy.

EXPERIMENTAL DESIGN:

[(18)F]FDG, [(18)F]FES, and [(18)F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen-deprivation therapy. Specificity of [(18)F]FFNP uptake in ERα(+) mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC).

RESULTS:

The levels of [(18)F]FES and [(18)F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen-deprivation therapy compared with those at pretreatment. In contrast, estrogen-deprivation therapy led to a reduction in PgR expression and [(18)F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [(18)F]FFNP tumor uptake, indicating that [(18)F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen-deprivation therapy.

CONCLUSIONS:

Monitoring the acute changes in ERα activity by measuring [(18)F]FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [(18)F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment.

• Authors: Szeman Ruby Chan, Amy M Fowler, Julie A Allen, Dong Zhou, Carmen S Dence, Terry L Sharp, Nicole M Fettig, Farrokh Dehdashti, John A Katzenellenbogen
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 5 Pg. 1063-70 (Mar 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25520392 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Hormonal
• Biomarkers
• ESR1 protein, human
• Estrogen Receptor alpha
• Ligands
• Receptors, Progesterone
• Fluorodeoxyglucose F18
• Promegestone

Topics

• Animals
• Antineoplastic Agents, Hormonal (administration & dosage, pharmacology)
• Biomarkers
• Breast Neoplasms (diagnosis, drug therapy, genetics, metabolism)
• Cell Line, Tumor
• Diagnostic Imaging
• Disease Models, Animal
• Drug Resistance, Neoplasm
• Estrogen Receptor alpha
• Female
• Fluorodeoxyglucose F18
• Humans
• Ligands
• Mammary Neoplasms, Experimental
• Mice
• Positron-Emission Tomography
• Promegestone (pharmacology)
• Receptors, Progesterone (metabolism)
• Tomography, X-Ray Computed